Earlier generation compounds of nitrogen-containing bisphosphonates such as pamidronate (Aredia®), alendronate (Fosamax®), risedronate (Actonel®), zoledronate (Zometa®), and ibandronate (Boniva) represent drugs currently used to treat conditions such as osteoporosis, Paget's disease and hypercalcemia due to malignancy. These compounds function primarily by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), resulting in decreased levels of protein prenylation in osteoclasts. Certain bisphosphonates have also been found to have anti-parasitic activity and to stimulate human γδ T cells, and with these earlier generation compounds there has been interest in cancer-related applications. There is a continued need, however, for the further development of alternative compounds and methods of use including therapeutic applications. There remains a need for alternative compounds and methods, including in particular compounds having improved properties such as greater activity and/or other advantageous functionality.
The mevalonate pathway, also referred to as the HMG-CoA reductase pathway, or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in higher eukaryotes and many bacteria. This pathway contributes to the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) that serve as the basis for the biosynthesis of molecules used in processes as diverse as protein prenylation, cell membrane maintenance, hormones, protein anchoring and N-glycosylation. The ability to inhibit a single molecule in such a pathway can provide an option for the modification of function and one or more outputs of the pathway. The ability to interact with multiple molecular targets of such a fundamentally important pathway, however, can provide opportunities for greater levels of modification. For example, the ability to simultaneously knock out a pipeline at several points can dramatically diminish the impact of the pipeline's flow and/or yield of products.
In embodiments of the invention herein, we disclose important discoveries regarding compounds and methods in connection with the inhibition of molecular targets including FPPS, geranylgeranyl pyrophosphate synthase (GGPPS), and decaprenyl pyrophosphate synthase (DPPS).
In certain embodiments, compounds of the invention include bisphosphonates that are capable of selectively inhibiting one or more of FPPS, GGPPS, and DPPS. In preferred embodiments, compounds of the invention are capable of selectively inhibiting two or more of FPPS, GGPPS, and DPPS. In embodiments, compounds and methods of the invention demonstrate superior activity levels, such as in the anti-cancer context, which in several cases exceed the activity levels of previous generation bisphosphonate drugs by orders of magnitude. The invention disclosed herein thus represents a major advance in the development of useful agents which in certain embodiments are compounds capable of demonstrating high potency levels.